The clinical course of HIV infection is unpredictable and highly variable. HIV infected persons may live without symptoms for years or may succumb to opportunistic infections or cancer within a short time. We propose to study the controlling factors in the immune response to the HIV at the level of idiotypic network. Since the immune response to HIV is like any other immune response under network control, analysis of the idiotype/anti- idiotype interactions in the patient reflects the immunological state in the disease and provides useful parameters for predicting the further course of the infection. Specifically, we will analyze the immune response to the gp120 envelope in HIV positive individuals, ARC and AIDS patients. Antibodies against gp120 from these groups will be immortalized by "rescue" human-mouse fusion. Monoclonal mouse anti-idiotypic antibodies will be generated against these human anti-gp120 antibodies. These monoclonal anti-idiotypes will be used as probes for the idiotype regulatory network in HIV individuals and patients. Human sera from HIV positive individuals and patients will be screened for binding to monoclonal anti-idiotype probes by ELISA and Western blots after isoelectrofocusing. Inhibition of anti-idiotype binding in the presence of gp120 protein will indicate which of these idiotopes are regulatory (Ag-, Id+). By employing a panel of anti- idiotypes we will try to establish correlations between expression of idiotypes and the clinical stage. Such correlations will produce predictive parameters for the course of the HIV infection. The role of the genetic variability of the HIV envelope in the idiotype network control will be addressed by isolating a panel of HIV gp120 variants from patients under study and by using vector expression envelope proteins from the different prototype sequence variants (see Project 1). Variant gp120 will be used to "rescue" human anti-gp120 antibodies and to generate anti- idiotypes. These studies will provide important information on the immunological state of the HIV infected patient and thus will produce predictive parameters for the future course of the disease. Although the analysis of the idiotypic regulation will be done initially on a small number of patients correlative trends in idiotypic patterns with disease stage are expected. The panel of anti-idiotypic and idiotypic probes will then be made available to other AIDS research centers for further testing. Predictive data will be useful in choosing appropriate anti-viral or other therapies.